Oxygen, hypoxia and the stem cell niche

Oxygen in Stem Cell Biology: A Critical Component of the Stem Cell Niche by Ahmed Mohyeldin, Tomás Garzón-Muvdi and Alfredo Quiñones-Hinojosa, Cell Stem Cell 2010(Aug 6); 7(2): 150-61. Review. [PubMed citation][FriendFeed entry]. Via Twitter @CellStemCell: Access [to the full text] is free in August worldwide so readers can try out new enhanced online format.

Abstract:

The defining hallmark of stem cells is their ability to self-renew and maintain multipotency. This capacity depends on the balance of complex signals in their microenvironment. Low oxygen tensions (hypoxia) maintain undifferentiated states of embryonic, hematopoietic, mesenchymal, and neural stem cell phenotypes and also influence proliferation and cell-fate commitment. Recent evidence has identified a broader spectrum of stem cells influenced by hypoxia that includes cancer stem cells and induced pluripotent stem cells. These findings have important implications on our understanding of development, disease, and tissue-engineering practices and furthermore elucidate an added dimension of stem cell control within the niche.

Differences that separate normal vs cancer SC molecular circuitry

Pluripotent Transcription Factors Possess Distinct Roles in Normal versus Transformed Human Stem Cells by Junfeng Ji, Tamra E Werbowetski-Ogilvie, Bonan Zhong, Seok-Ho Hong and Mickie Bhatia, PLoS ONE 2009(Nov 30); 4(11): e8065 [FriendFeed entry][Full text is publicly accessible (via Libre OA)]. PubMed Abstract:

BACKGROUND: Cancer and normal stem cells (SCs) share proliferative properties of self-renewal and expression of key transcription factors (TFs). Despite similar TF identities, the functional role of specific TFs responsible for retaining SC state has yet to be examined in cancer. METHODOLOGY/PRINCIPAL FINDINGS: Here, we compare the role of Oct4 and Nanog, two-core pluripotent TFs, in transformed (t-hPSCs), and normal human pluripotent stem cells (hPSCs). Unlike normal SCs, self-renewal and survival of t-hPSCs were found to be independent of Oct4. In contrast, t-hPSCs exhibit hypersensitivity to reduction in Nanog and demonstrate complete loss of self-renewal coupled with apoptosis. Dual and sequential knockdown of Oct4 and Nanog revealed that sensitivity of t-hPSCs to Nanog was Oct4 dependent. CONCLUSIONS/SIGNIFICANCE: Our study indicates a bifurcation for the role of two-core SC and cancer related TFs in self-renewal and survival processes. We suggest that the divergent roles of these TFs establish a paradigm to develop novel therapeutics towards selective destruction of aggressive tumors harboring cancer stem cells (CSCs) with similar molecular signatures.

Researchers find new kind of prostate SC in mice

New Type Of Adult Stem Cells Found In Prostate May Be Involved In Cancer Development, ScienceDaily, September 10, 2009. Excerpts:

The new study may resolve this conundrum because the newly discovered adult stem cells are also luminal cells. "Previous research suggested that prostate cancer originates from basal stem cells, and that during cancer formation these cells differentiate into luminal cells," said Dr. Shen. "Instead, CARNs may represent a luminal origin for prostate cancer" [CARNs stands for "castration-resistant Nkx3.1-expressing cells"].

And indeed, the researchers found that CARNs in mice can give rise to prostate cancers, after the cells lose the activity of PTEN, a gene that is frequently mutated in human prostate cancers.

See also: New Progenitor Cell in Mice Can Cause Prostate Cancer, Michael Smith, Medpage Today, September 9, 2009; Researchers find prostate cancer stem cell, Reuters, September 9, 2009.

These news items are about the publication: A luminal epithelial stem cell that is a cell of origin for prostate cancer by Xi Wang and 9 co-authors, including Michael M Shen, Nature 2009(Sep 9) [Epub ahead of print][PubMed Citation].

Comment: These CSCs were found in mice, and "it is unclear whether CARNs exist in the normal human prostate and if human prostate cancers can originate from these CARNs" (see last paragraph of the Medpage Today article).

Found via: Two Studies Make Promising Advances in Prostate Cancer Research, Denis Cummings, FindingDulcinea, September 10, 2009.

A neurosurgeon's guide to CSC

A neurosurgeon's guide to stem cells, cancer stem cells, and brain tumor stem cells by Samuel H Cheshier and 5 co-authors, including Irving L Weissman, Neurosurgery 2009(Aug); 65(2): 237-49. PubMed Abstract:

Stem cells and their potential applications have become the forefront of scientific, political, and ethical discourse. Whereas stem cells were long accepted as units of development and evolution, it is now becoming increasingly clear that they are also units of oncogenesis. Although the field of stem cell biology is expanding at an astounding rate, the data attained are not readily translatable for the physicians who may eventually deliver these tools to patients. Herein, we provide a brief review of stem cell and cancer stem cell biology and highlight the scientific and clinical implications of recent findings regarding the presence of cancer-forming stem cells in brain tumors.

MicroRNAs play roles in glioma stem-like cell behavior?

A review: MicroRNAs and glioblastoma; the stem cell connection by Jakub Godlewski and 4 co-authors, including Sean E Lawler, Cell Death Differ 2009(Jun 12) [Epub ahead of print][Entry in FriendFeed] PubMed Abstract:

Recent data draw close parallels between cancer, including glial brain tumors, and the biology of stem and progenitor cells. At the same time, it has become clear that one of the major roles that microRNAs play is in the regulation of stem cell biology, differentiation, and cell 'identity'. For example, microRNAs have been increasingly implicated in the regulation of neural differentiation. Interestingly, initial studies in the incurable brain tumor glioblastoma multiforme strongly suggest that microRNAs involved in neural development play a role in this disease. This encourages the idea that certain miRs allow continued tumor growth through the suppression of differentiation and the maintenance of the stem cell-like properties of tumor cells. These concepts will be explored in this article.Cell Death and Differentiation advance online publication, 12 June 2009; doi:10.1038/cdd.2009.71.

SC markers invention

United States Patent Application 20090012024, Anne Collins, Norman Maitland, Steven Bryce, January 8, 2009. [See also: Stem Cell Markers and Stem cell markers]. Abstract:

We disclose gene markers of stem cells, typically prostate stem cells, and in particular cancer stem cells, for example prostate cancer stem cells; therapeutic agents and diagnostic assays based on said stem cell genes; and including screening assays to identify therapeutic agents.

Excerpt:

[0030]We have conducted gene array analysis to identify genes that are characteristic of cancer stem cells which show an up regulation when compared to control stem cell samples from normal or benign stem cell populations. We herein disclose these genes and their use in the identification of therapeutic agents useful in the treatment of cancer, in particular prostate cancer, and in the development of diagnostic assays for the detection of the early on set of tumour cell growth. The present disclosure relates to the identification of cancer stem cell specific genes.

An earlier Patent Application: 20080233640, Norman James Maitland, Anne Collins, September 25, 2008. [See also: Prostate Stem Cell and Prostate stem cell]. Abstract:

We describe a method for the isolation of prostate stem cells, typically prostate stem cells which express CD 133 antigen; stem cells and cancer stem cells isolated by the method and their use.

Two recent publications from this research group [not publicly accessible]:

Inflammation as the primary aetiological agent of human prostate cancer: a stem cell connection? Norman J Maitland, Anne T Collins, J Cell Biochem 2008(Nov 1); 105(4): 931-9 [PubMed Citation].

Prostate cancer stem cells: a new target for therapy, Norman J Maitland, Anne T Collins, J Clin Oncol 2008(Jun 10); 26(17): 2862-70 [PubMed Citation].

A recent news item:

Investors back their belief in biotech company by Bernard Ginns, Yorkshire Post, January 20, 2009. Excerpts:

Pro-Cure's expertise is in the culture, isolation, handling and gene profiling of human prostate cancer stem cells. It is working with a number of big pharmaceutical firms in this burgeoning area.

Its management team includes Professor Norman Maitland, director of Yorkshire Cancer Research and professor of molecular biology at the University of York, who is regarded as one of the world leaders in his field.

The website for Pro-Cure Therapeutics includes a page about the Management Team.

Comparing SC from the adult human brain and from brain tumors

A comparison between stem cells from the adult human brain and from brain tumors by Mercy Varghese and 8 co-authors, including Iver A Langmoen, Neurosurgery 2008(Dec); 63(6): 1022-34 [PubMed Citation].

Evaluation: Tali Siegal: Faculty of 1000 Medicine, 6 Jan 2009. Excerpt:

This study provides further evidence in support of the theory of human brain tumors deriving from apparent stem cell populations, rather than from transformation and differentiation of glial cells. The implication is that glioma stem cells should become the targets of future therapies, and, to that end, understanding the differences between normal and abnormally derived cells is important.

Minireview: PTEN, SC , and CSC

PTEN, stem cells, and cancer stem cells by Reginald Hill and Hong Wu, J Biol Chem 2008(Dec 30) [Epub ahead of print]. [Accepted Manuscript] PubMed Abstract:

Like normal stem cells, "cancer stem cells" (CSCs) have the capacity for indefinite proliferation and generation of new cancerous tissues through self-renewal and differentiation. Among the major intracellular signaling pathways, Wnt, Shh, and Notch are known to be important in regulating normal stem cell activities and their alterations are associated with tumorigenesis. It has become clear recently that phosphatase and tensin homologue (PTEN) is also critical for stem cell maintenance and that PTEN loss can cause the development of CSCs and ultimately tumorigenesis.

Stem cell gene expression: human squamous cell carcinomas

A stem cell gene expression profile of human squamous cell carcinomas, Kim B Jensen, Judith Jones, and Fiona M Watt, Cancer Lett 2008(Dec 8); 272(1): 23–31 [PMC version]. PubMed Abstract:

To investigate the relationship between stem cells in normal epithelium and in squamous cell carcinomas (SCCs), we examined expression of a panel of human epidermal stem cell markers in SCCs and SCC cell lines. Markers that are co-expressed in normal stem cells were not co-expressed in SCC. Downregulation of two markers, Lrig1 and MAP4, and upregulation of a third, MCSP, correlated with poor differentiation status and increased proliferation in primary tumours. We conclude that SCCs do not reflect a simple expansion of stem cells; rather, tumour cells hijack the homeostatic controls that operate in normal stem cells, eliminating those that maintain stem cell quiescence.

Last paragraph of the Discussion section:

In conclusion, our data favour a model whereby during tumour development the pathways that control epithelial homeostasis are lost, particularly in the basal cell layer closest to the tumour stroma. Those markers of normal stem cells that exert a positive effect on proliferation or inhibit differentiation are upregulated, while those that normally retain the cells in a nondividing state show reduced expression. As we find out more about how different signalling pathways intersect to maintain homeostasis we will have more opportunities for restoring homeostasis in tumours.

[This is a Sponsored Article. The PMC version may be redistributed and reused, subject to certain conditions].

ASH 50th Anniversary Review by John Dick

Stem cell concepts renew cancer research by John E Dick, Blood 2008(Dec 15);112(13): 4793-4807. Abstract:

Although uncontrolled proliferation is a distinguishing property of a tumor as a whole, the individual cells that make up the tumor exhibit considerable variation in many properties, including morphology, proliferation kinetics, and the ability to initiate tumor growth in transplant assays. Understanding the molecular and cellular basis of this heterogeneity has important implications in the design of therapeutic strategies. The mechanistic basis of tumor heterogeneity has been uncertain; however, there is now strong evidence that cancer is a cellular hierarchy with cancer stem cells at the apex. This review provides a historical overview of the influence of hematology on the development of stem cell concepts and their linkage to cancer.

One of the most recent of the 50th Anniversary Reviews of the American Society of Hematology (ASH).

Guidelines for the Clinical Translation of SC

Guidelines for the Clinical Translation of Stem Cells, International Society for Stem Cell Research (ISSCR), December 3, 2008. Links are provided to the Guidelines [PDF], to Apppendix 1 (a Patient Handbook on Stem Cell Therapies) [PDF], to Appendix 2 (Additional Resources), to a Cell Stem Cell article summarizing the essential elements of the document [PubMed Citation] and to a joint ISSCR and Cell Stem Cell Press Release about the Guidelines.

For an article, in the same issue of Cell Stem Cell, that provides evidence that such Guidelines are needed, see: Stem Cell Clinics Online: The Direct-to-Consumer Portrayal of Stem Cell Medicine by Darren Lau and 5 co-authors, including Timothy Caulfield, Cell Stem Cell 2008(Dec 4); 3(6): 591-4. PubMed Abstract:

Despite the immature state of stem cell medicine, patients are seeking and accessing putative stem cell therapies in an "early market" in which direct-to-consumer advertising via the internet likely plays an important role. We analyzed stem cell clinic websites and appraised the relevant published clinical evidence of stem cell therapies to address three questions about the direct-to-consumer portrayal of stem cell medicine in this early market: What sorts of therapies are being offered? How are they portrayed? Is there clinical evidence to support the use of these therapies? We found that the portrayal of stem cell medicine on provider websites is optimistic and unsubstantiated by peer-reviewed literature.

See also: Laws needed to protect patients from stem cell clinics' exaggerated claims: study by Sheryl Ubelacker, Canadian Press, December 3, 2008. The first sentence:

Canadians should be "very skeptical" of foreign clinics that use websites to promote stem cell therapies for a wide range of medical conditions, warn researchers, saying there is a dearth of scientific evidence to back up their claims.

Comments: The Guidelines contain no explicit mention of cancer SC. However, if one accepts the prediction that "diagnostic methods based on the detection of CSC’s will have the potential to address key limitations of current methods" [excerpt from Business Wire, April 26, 2007], then some attention needs to be paid to the known limitations of diagnostic methods. Two examples of relevant references:

1) Grading quality of evidence and strength of recommendations for diagnostic tests and strategies by Holger J Schünemann and 10 co-authors, including Gordon H Guyatt, BMJ 2008(May 17); 336(7653): 1106-10 [PubMed Citation]. Excerpt from the publicly-accessible Extract:

Inferring from data on accuracy that a diagnostic test or strategy improves patient-important outcomes will require the availability of effective treatment, reduction of test related adverse effects or anxiety, or improvement of patients’ wellbeing from prognostic information.

Excerpt from the full text:

Although recommendations on diagnostic testing share the fundamental logic of recommendations on treatment, they present unique challenges.

2) See also: Evaluation of clinical innovation: a gray zone in the ethics of modern clinical practice? by Johane Patenaude and 4 co-authors, J Gen Intern Med 2008(Jan); 23(Suppl 1): 27-31 [PubMed Citation]. Excerpt for the Conclusions section of the (publicly accessible) full text:

Innovation is a neglected area for ethics assessment. Further studies on a larger scale are necessary to review the concepts of experimental, innovative, and commonly accepted care.

Perhaps a subsequent version of the ISSCR Guidelines should include a section on diagnostic tests involving CSC?

News release about microRNAs

UCSF team moves in on mechanism in stem cell growth, possibly cancer, News Release, UCSF News Office, November 13, 2008. Excerpt:

In recent years, microRNAs have been implicated in cancer stem cells, cancer metastases, and even in psychological and metabolic diseases.

The news release is about this publication: Embryonic stem cell–specific microRNAs regulate the G1-S transition and promote rapid proliferation by Yangming Wang and 5 co-authors, including Robert Blelloch, Nat Genet 2008(Nov 2) [Epub ahead of print]. [PubMed Citation]. The article isn't freely accessible.

UK/CIRM collaboration agreement

State, United Kingdom team for stem cell work by Bernadette Tansey, SFGate, October 21, 2008. Excerpts:

California's stem cell funding institute is teaming up with its United Kingdom counterpart to support research collaborations between scientists, the two government agencies said Monday.

.....

Under the new agreement, teams that include United Kingdom and California scientists will be able to file joint grant applications to the state's stem cell funding institute and the United Kingdom's Medical Research Council. For teams that win grants, the California institute will fund the work of the California members and the research council will pay for the research conducted in the United Kingdom.

.....

The state stem cell funding institute announced similar agreements in June with the Australian state of Victoria and Canada's Cancer Stem Cell Consortium. Victoria pledged $100 million to the effort.

Found via: UK, CIRM ink collaboration agreement by David Jensen, California Stem Cell Report, October 22, 2008.

See also: UK and California agree to collaborate on stem cell research by Monya Baker, The Niche, October 21, 2008. The first two paragraphs:

California’s stem cell funding agency signed a memorandum of understanding with the United Kingdom, expediting collaborations between scientists in the two locations.

Robert Klein, chair of the California Institute of Stem Cell Research and Lord Paul Drayson, UK’s Minister for Science, met in the San Francisco airport to sign the four-page document.

Stanford center for stem cell research

Lokey gives $75 million to create nation's largest stem cell research center at Stanford by Ruthann Richter (News Release, Office of Communication & Public Affairs, Stanford University Medical Center, October 6, 2008). Excerpts:

Lorry I. Lokey, the Business Wire founder and philanthropist, is giving $75 million to the Stanford University School of Medicine to help build what is expected to be the nation’s largest center for stem cell research, the medical school announced Oct. 6.

.....

His contribution will help build a new home for the Stem Cell Biology and Regenerative Medicine Institute, one of five major research institutes based in the medical school. Institute scientists are involved in the full array of stem cell research, including studies in both embryonic and adult cells, as well as work in cancer stem cells and in the development of disease-specific stem cell lines.

.....

“Scientists in the fields of stem cell and cancer research are on the brink of new discoveries that may soon affect the understanding and treatment of disease,” said Irving Weissman, MD, the Virginia and D.K. Ludwig Professor for Clinical Investigation in Cancer Research and director of Stanford’s stem cell institute. “With this magnificent lead gift from Lorry Lokey, Stanford will have the facilities to lead those efforts.”

Weissman, who was the first to isolate stem cells in both mice and humans, said the availability of new space will attract key faculty to Stanford and spur collaborations with scientists from the around the world. The new center will include 60 laboratory benches for scientists who will visit Stanford for a month or a year at a time. Lokey said the prospect of bringing top research talent to Stanford is far more meaningful to him than any worldly goods his money could buy.

“I don’t want airplanes and boats and country club memberships,” he said. “I believe that if you fall into a lot of money like I did, you put it into the soil—you replenish the soil for next year’s crop.”

Found via MarketWatch, Oct 06, 2008.

Two blog posts about cancer stem cells

Two recent blog posts by Kevin Graham (thanks to Drew Lyall):

1) Meet Kevin Graham: Cancer stem cell researcher, Connecting for Kids, September 19, 2008. Excerpt:

Have you ever heard of tumour stem cells? Did you know that stem cell research is being used to search for a cure for brain tumours? Admittedly, these probably aren’t the first things that jump to your mind when you hear about stem cell research, but that’s exactly why we started this forum.

2) Stem cells, Cancer and Cancer Stem Cells, Connecting for Kids, September 24, 2008. Excerpt:

How do you target a cancer stem cell? This is one of the many ways in which stem cell research is paying off. Early indications are that normal stem cells and cancer stem cells share many of the same cellular processes. Research over the years has compiled an amazing amount of data about how normal stem cells function, information that is now being rapidly applied to cancer stem cells.

The right frame of both posts also includes links to brief profiles of three other stem cell researchers at the Hospital for Sick Children (SickKids) in Toronto: Janet Rossant (mammalian developmental biology and genetics), Peter Dirks (cancer stem cells of brain tumors) and Freda Miller (neuronal stem cells and neuronal growth, survival and apoptosis).

PTEN and planarian stem cells

A recent news item: Flatworms can shed new light on cancer, stem cells, News Track India, Sep 18, 2008. Excerpts:

During a study, scientists at the University of Utah and the Forsyth Institute at Harvard found that the flatworm contains a gene highly similar to the human gene PTEN, which is often found to be mutated in cancer cases.

.....

The study has been published in the journal Disease Models and Mechanisms (DMM).

The article is: Planarian PTEN homologs regulate stem cells and regeneration through TOR signaling, Néstor J. Oviedo, Bret J. Pearson, Michael Levin and Alejandro Sánchez Alvarado, Dis. Model. Mech. 2008(Sep 18), doi:10.1242/dmm.000117

The last sentence of the Abstract:

Altogether, our data reveal roles for PTEN in the regulation of planarian stem cells that are strikingly conserved to mammalian models. In addition, our results implicate this protein in the control of stem cell maintenance during the regeneration of complex structures in planarians.

For information about this new journal, see: Disease Models & Mechanisms (DMM), NewJour, August 7, 2008. Excerpt:

To ensure the wide dissemination of all authors' work during the launch year, DMM has made a commitment to provide immediate, unrestricted online access to all articles from Volume 1 on the journal website.

Cancer spread and stem cells

There's an article, "Breakthroughs seen in cancer spread and stem cells", by Carey Goldberg of The Boston Globe, September 9, 2008. Excerpts from the first page:

Mani and his colleagues at the MIT-affiliated Whitehead Institute found what appears to be a key to metastasis, the insidious process by which cancer spreads throughout the body and often kills. And, in a surprising spinoff, that same discovery also may lead to a relatively safe, simple way to transform normal adult cells into stem cells that could be used to treat other diseases.

The scientists believe their one-step method may avoid the risk of random mutation (and possibly cancer), a stumbling block for therapies based on other recently developed techniques for creating stem cells.

Excerpts from the second page of the same article:

For all his excitement, Weinberg readily acknowledged that Mani's line of investigation has yet to produce a "gold-standard proof" that the stem-like cells are actually stem cells. If their thinking is correct, he said, it should be possible to induce the key metamorphosis in some breast cells of one mouse, place them in another mouse's chest and develop a breast.

The experiment worked once, he said, but his lab has been unable to replicate it and ended up publishing its work in the leading biology journal Cell this May without that crowning proof.

The publication in Cell isn't cited, but it appears to be this one: "The epithelial-mesenchymal transition generates cells with properties of stem cells", by Sendurai A Mani and 14 co-authors, including Robert A Weinberg, Cell 2008(May 16); 133(4): 704-15 [PubMed Abstract]. Unfortunately, the publication isn't freely accessible.

It's been cited by a more recent article (also not freely accessible): "Epithelial-mesenchymal transition and the stem cell phenotype", by Derek C Radisky and Mark A LaBarg, Cell Stem Cell, 2008(Jun 5); 2(6): 511-2 [PubMed Abstract]. The Abstract:

Epithelial-mesenchymal transition (EMT) is a developmental process in which epithelial cells acquire the motile, migratory properties of mesenchymal cells. In a recent issue of Cell, Mani et al. (2008) show that induction of EMT stimulates cultured breast cells to adopt characteristics of stem cells.

A brief excerpt from the full text:

An exciting implication of these results is that there may be a direct relationship between EMT and the phenomenon of CSCs.

Comments on these articles would be welcomed.